This invention relates to the field of purification of liquids, and specifically to the purification of liquids by the removal of metals therefrom.
It is well known that exposure to certain metals and metal-containing substances causes a variety of ill effects on health. Such exposure occurs by inhalation, ingestion, injection, or any other means through which people and other organisms come into contact with metals or metal-containing substances. Substantial benefits would therefore accrue from the removal of metals from certain substances in order to minimize the harmful effects of metal exposure on people and other organisms.
The deleterious effects of metal exposure range from the temporary respiratory irritation that can result from inhaling an inert metal powder to more serious effects including skin rashes, asthma, allergies and sensitization, headaches, nausea and vomiting, changes in blood pressure and/or heart rate, damage to the heart, damage to the kidneys and/or liver, neurological damage, anemia, and reproductive disorders. Some metals, such as chromium (VI), are well-known mutagens, teratogens, and/or carcinogens. Some metals, such as radium and plutonium, are hazardous because of their radioactivity. Exposure to certain metals, such as arsenic or thallium, can be fatal.
In addition, some metals are known to bio-accumulate. That is, the exposed organism has no mechanism, or only inefficient mechanisms, for excreting the metal. As a consequence, the metal remains in the organism at a level that increases with each additional exposure. Mercury is one well-known bio-accumulating toxic metal.
Aside from health and environmental concerns, there may be other reasons for rendering a particular substance free of metals. For example, the efficient recovery of precious metals is an economically beneficial goal. Also, the presence of paramagnetic or colored metals might interfere with the spectroscopic or spectrophotometric analysis of other materials.
Palladium is a metal that is commonly used in redox catalysis. Palladium-mediated cross-couplings are also of great significance in the synthesis of organic compounds, because such reactions are highly versatile and represent an important means of carbon-carbon bond formation. Palladium containing catalysts may be homogeneous, i.e., soluble in the reaction medium, or heterogeneous. Heterogeneous catalysts may be bulk metals, alloys, or compounds. Heterogeneous palladium catalysts may also comprise a thin layer of active metal, alloy, or compound on a solid support. Other heterogeneous catalysts include palladium bound to one or more ligands immobilized on a solid support. See, e.g., U.S. Pat. No. 6,232,262.
The products of palladium catalyzed or mediated reactions, however, may require further reactions or processing with which residual palladium would interfere. Alternatively, the products may be organic compounds such as drug substances, which, if containing palladium when administered, could cause the patient to be exposed to a heavy metal with potentially toxic effects. Therefore, a particular need exists for efficient processes to remove palladium from organic compounds and liquids containing organic compounds, e.g., the reaction media in which they are produced.
Many methods have been developed to reduce the level of residual palladium in organic processes. The removal of even small amounts of palladium can pose difficulties, however. The traditional approach to removing impurities, that is, selective crystallization of the organic product, often fails to reduce palladium to the level of parts per million, which is highly desirable or even essential for the preparation of drug substances.
One generally applicable strategy is to use the smallest amount of palladium possible in the reaction mixture, thus decreasing the total amount of palladium to be removed from the final product. Another general approach is to re-position palladium catalyzed reactions from the final steps to the earlier steps in the synthetic sequence. The idea behind this strategy is that the processing of subsequent intermediates will reduce the level of residual palladium in the final product, if for no other reason than dilution alone. (Maryanoff, C. A., et al., in Catalysis of Organic Reactions; Rylander, P. N., Greenfield, H., Augustine, R. L., Eds.; Marcel Dekker, New York, 1988; pp 368-375; Anderson, N. G., et al. Org. Process Res. Dev. 1997, 1, 300.) Electrolytic plating is another commonly practiced method of removing palladium from liquids.
Other approaches for palladium removal can be divided into two categories: extraction and precipitation treatments, and solid phase treatments. The chemistry of the extraction of metals into organic solvents using, e.g., β-hydroxy ketones, 8-hydroxyquinoline, 8-mercaptoquinoline, oximes, hydroxylamines, sodium diethyldithiocarbamate, and others has been reviewed extensively. (De, A. K., et al. Solvent Extraction of Metals; Van Nostrand Reinhold Company: New York, 1980.) Trimercaptotriazine (TMT) has also been used to remove palladium from organic reaction mixtures. (Rosso, V. W., et al., Org. Proc. Res. Dev., 1997, 1, 311-314.)
Other examples of methods of removing palladium by extraction from a liquid medium include the use of ligands such as amines, aniline, pyridine, ethylenediamine tetraacetic acid, carboxylates, cyanides, thiocyanates, acetylacetonates, N,N-diethyl-dithiocarbamic acid and the like, triaryl phosphines, and bidentate phosphines (Van Broekhoeven, EP 028392; Pino et al., EP 0285218); N,N-dimethyldithiocarbamoylethoxy-substituted calix[4]arene (Yordanov, A. T., et al. Inorg. Chim. Acta 1995, 240, 441.); sulfur-based ligands, e.g., nonylthiourea, dodecylthiourea, triisobutylphosphine sulfide, and thiocrown ethers (Zuo, G.; Muhammed, M. Solvent Extr. Ion Exch. 1995, 13 (5), 879; Shukla, J. P., et al. Nucl. Sci. J. 1996, 33 (1), 39.); TOA-kerosin (Lingen, J., et al., He Huaxue Yu Fangshe Huaxue, 1986, 8(2), 108-112); and [[N,N-bis(2-ethyl-1-hexyl)amino]methyl]phosphonic acid (Baba, Y., et al. J. Solvent Extr. Res. Dev., Jpn. 1995, 2, 93.). Hydrazine is a highly effective reagent for the precipitation of palladium from a nitric acid solution. (Chung, D. Y., et al. J. Radioanal. Nucl. Chem. Articles 1996, 204(2), 265.)
Some of the solid phase treatments for the removal of palladium from a liquid medium are quite simple, for example, physical separation by filtration. Such an approach would be especially effective for removing precipitates or heterogeneous catalysts from solution.
Non-selective adsorption of impurities, e.g., filtration through activated carbon, is another commonly practiced solid phase treatment. See, e.g., Japanese Patent No. 53067619. In some cases, the activated carbon has been used in combination with other solids, for example, iron sulfide, silica gel, diatomaceous earth, or polyacrylamide (Japanese Patent No. 52126685). Activated carbons modified with dimethylglyoxime (Foersterling, H.-U., Carbon, 1990, 28, 27-34.) or with alpha-dioxime (Japanese Patent No. 53067620) have also been used to sequester palladium.
Other solid phase treatments include iminodiacetic acid resins, which selectively bind divalent cations. For example, Chelex 100, a resin available from Bio-Rad Laboratories in Richmond, Calif., has a greater affinity for palladium (II) than for copper (II) in acetate buffer (pH=5). See also German Democratic Republic Patent No. 107372 and Japanese Patent Nos. 03199392, 53006296, 59133389, and 60050193. The macroreticular cation exchange resin Dowex M-33, available from the Dow Chemical Co. of Midland, Mich., is also known to have a high affinity for palladium (II), as does Deloxan THP II, a thiourea-modified resin available from the Degussa Corporation of Parsippany, N.J. Polystyrene-bound trimercaptotriazine (TMT) has been used for like purposes (Ishihara, K., et al., Chem. Lett., 2000, 10, 1218), as has an insoluble aminoalkyl-substituted organopolysiloxane thiourea (U.S. Pat. No. 5,061,773). An ethylenediamine-modified macroporous copolymer of glycidylmethacrylate and ethylenedimethacrylate was used by Radova et al. to remove palladium (II) from aqueous HCl and KCl solutions. Angew. Makromol. Chem., 1979, 81, 55-62.
Anion exchange resins have also been used for the removal of metals, including palladium, from liquids. See, e.g., U.S. Pat. No. 3,656,939. An anion exchange resin containing benzimidazoles and quaternary benzimidazolium species has been used to remove palladium ions from nitric acid solutions. (Wei, Y. Z., et al. Spec. Publ.-R. Soc. Chem. 1996, No. 182 (Ion Exchange Developments and Applications), 174.) A tertiary pyridine type anion exchange resin was shown to have a good affinity for palladium under acidic conditions. (Nogami, M., et al., Nucl. Technol. 1996, 115, 293.)
Other solids used in the removal of palladium include carbonaceous pyropolymers, which are known to remove palladium from aqueous solutions by reducing palladium ions, thereby plating palladium metal onto the pyropolymer itself. (Rosin, R. R.; Schwerin, W. C., U.S. Pat. No. 5,458,787; Makita, Y., et al. Japanese Patent JP 89-128533 (Chem Abstr. 1991, 115, 17573e).) A magnetic chelating resin with a high content of sulfur and nitrogen atoms was shown to be effective for the removal of palladium ions under acidic conditions. (Wen, D. et al., J. Wuhan Univ. Technol., Mater. Sci, Ed. 1994, 9, 54; Chem. Abstr. 1995, 123, 341826.) Chromatography on silica gel has been used to remove spent palladium (0) catalyst from reaction mixtures (U.S. Pat. No. 6,291,722). Palladium has been removed by contact with silica gel or other solids whose surfaces have been silanized, then aminated, before functionalization with a variety of palladium binding moieties, such as carboxylates, thiols, amines, imines, phosphines, thiocyanates, isothiocyanates, cyanates, and isocyanates. (U.S. Pat. Nos. 5,695,882 and 5,997,748.) A chemically active ceramic composite material containing thiol and amine moieties is known to remove metal ions from solution. (Tavlarides, L. L.; Deorkar, N., PCT Int. Appl. WO9609985 A1.) Composites of calcium alginate polymer gels with copper ferrocyanide selectively adsorbed palladium (II) from solutions designed to simulate radioactive waste. (Mimura, H., et al., Tohoku Daigaku Sozai Kogaku Kenkyusho Iho, 2000, 56, 1-8.)
Several methods of removing palladium through the use of abundant and economical solid biomaterials have also been developed. The chicken feather, an intricate network of stable, water insoluble protein fibers with high surface area, is one such useful biomaterial. It has been reported that chicken feathers can absorb an amount of palladium equal to 7% of their dry weight. (Suyama, K. et al. Appl. Biochem. Biotechnol. 1996, 57/58 (Seventeenth Symposium on Biotechnology for Fuels and Chemicals, 1995), 67.) Bacteria immobilized in a tubular membrane reactor have also been used to recover palladium. (Diels, L., et al., J. Membr. Sci. 1995, 100, 249.) Other biomaterials useful in palladium removal include chicken eggshell membrane (Suyama, K. et al. Appl. Biochem. Biotechnol. 1994, 45-46, 87.), wool and silk (Masri, S. M., et al. W. Polym. Prepr., Am. Chem. Soc., Div. Polym. Chem. 1975, 16, 70), and the roots of various plants, including sunflowers, terrestrial turf grasses, and members of the family Brassicaceae. (Raskin, I. et al. PCT Int. Appl. WO94/29226 A1; Chem. Abstr. 1995, 122, 169223.)
Despite the techniques listed above, there nevertheless exists a need for efficient and effective processes for the removal of metals from various liquid media. Moreover, there is a particular need for processes that are capable of removing palladium from liquids that contain drug substances.